SUMMARY: Photoreceptor cell death is the ultimate cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective therapies to improve their survival. The bioenergetic requirements of photoreceptors rival that of neoplastic tissue. To meet this demand, photoreceptors have unique metabolic adaptations to budget their bioenergetic needs. One such adaptation is the utilization of aerobic glycolysis, so glucose metabolism has been central in the study of photoreceptor physiology. Even so, fuels other than glucose may be used to meet the needs of photoreceptors, especially during times of bioenergetic stress. Given their crowded, nutrient-limited environment, photoreceptors may have evolved to remove any rigid constraints on fuel sources. This proposal will provide fundamental insight into the contribution of a potential alternative fuel source to photoreceptor metabolism, function, and survival, while providing the substrate for critical skills in career development. The long-term goal of this work is to develop the skills needed to pursue novel therapies that prevent vision loss in photoreceptor degenerations as an independent clinician-scientist. The scientific objective of this K08 proposal is to test the hypothesis that glutamine is a key fuel source to maintain photoreceptor biomass, regulate redox balance, and boost photoreceptor survival during periods of nutrient deprivation. We propose to assess the metabolic fate of glutamine in vitro and in vivo using stable-isotope metabolic flux analysis and its contribution to photoreceptor redox balance, function, and survival by disrupting glutamine catabolism in a photoreceptor-specific, glutaminase (Gls) conditional knockout mouse. Two focused specific aims will be utilized to investigate our hypothesis: 1) Determine how glutamine contributes to components of photoreceptor biomass and regulates redox homeostasis.; 2) Determine how photoreceptors utilize glutamine as an alternative fuel source to promote survival during outer retinal stress. The career development objective is to cultivate the skills and mentorship required to develop expertise in the application, acquisition, and analysis of metabolomics data, and to achieve scientific independence. The coursework, seminars, and mentorship will complement the research. The multi- disciplinary team of mentors, each with a complementary skill set, is deeply committed to the principal investigator?s success. The Department of Ophthalmology and Visual Sciences and the University of Michigan has world-class faculty and facilities, and the research proposed fits exceptionally well with the internationally recognized expertise in metabolism and metabolomics at the University of Michigan and within the mentoring team. The institutional environment, mentoring, and career development plan maximize the success of the research aims and the ability of the principal investigator to become an independent clinician-scientist studying the interface of photoreceptor metabolism and survival to develop novel therapeutic paradigms that prevent vision loss in retinal disorders.